Antioxidants FACILITATE cancer growth

This should be the death-knell of the antioxidant religion. The authors below are of course careful to give believers an "out" of sorts and caution is proper but in conjunction with some previous studies (see side-column) which have shown harm from antioxidant intake, the warning is loud and clear

Cells don't like to be alone. In the early stages of tumor formation, a cell might be pushed out of its normal home environment due to excessive growth. But a cell normally responds to this homeless state by dismantling its nucleus, packing up its DNA, and offering itself to be eaten by immune system cells. Simply put, the homeless cell kills itself. This process, known as apoptosis, typically stops potential cancer cells before they have a chance to proliferate.

Now, researchers from the lab of Harvard Medical School professor of cell biology Joan Brugge have uncovered another mechanism that kills these precancerous, homeless cells. By studying two different types of human breast epithelial cells, the researchers found that when separated from their natural environment, these cells lose their ability to harvest energy from their surroundings. Eventually, they starve.

"We originally thought that in order for cells to survive outside their normal environment, they would simply need to suppress apoptosis," says Brugge, senior author on the paper, which appeared August 19 online in Nature. "But our studies indicate that this activity is not sufficient to prevent the demise of homeless cells. Even if they escape apoptosis, these cells can't transport enough glucose to sustain an energy supply."

Surprisingly, metabolic function is restored if antioxidant activity is increased inside the cells, allowing the cells to use energy pathways that don't rely on glucose. "It raises the interesting idea that antioxidants, which are typically thought to be protective because they prevent genomic damage, might be allowing these potentially dangerous cells to survive," says first author Zachary Schafer, assistant professor at the University of Notre Dame and a former postdoc in Professor Brugge's lab.

The authors caution against extrapolating too far from their data, which were based on experiments in laboratory cell culture. They also emphasize that the experiments were not designed to mimic the effect of dietary antioxidants in the body. The researchers used two specific antioxidant compounds - which are chemically distinct from those found in food and supplements - only in order to understand how oxidants contributed to the metabolic defects.

"We think that genes with antioxidant activity play a much bigger role than antioxidant compounds administered from outside the body," says Brugge. "What happens with dietary antioxidants is much more complicated and not what we were trying to study."

The researchers had previously reported that when cells were endowed with a cancer-causing gene that prevents them from committing suicide, they still died when cut off from their extracellular environment. This puzzled researchers, who have long thought that apoptosis was the only way the cells could die.

In the recent study, Schafer and colleagues took a closer look, measuring the levels of proteins and molecules associated with metabolic activity in the displaced, but apoptosis-resistant, cells. They found that the cells had become incapable of taking up glucose, their primary energy source. Under the microscope, the cells also displayed telltale signs of oxidative stress, a harmful accumulation of oxygen-derived molecules called reactive oxygen species (ROS). The end result was a halt in the production of ATP, the molecular lifeblood that transports energy in the cells. The unmoored cells were literally starving to death. "The idea that a lack of extracellular matrix can prevent cells from accessing nutrients hasn't been shown conclusively before," says Schafer. "Loss of glucose transport, decreased ATP production, increased oxidative stress - all those things turn out to be interrelated."

To figure out what was wrong, the researchers took a straightforward approach - they tried to fix it. Schafer engineered the homeless cells to express high levels of a gene, HER2, known to be hyperactive in many breast tumors. He also treated the cells with antioxidants in an attempt to relieve oxidative stress and help the cells survive.

Both strategies worked. The cells with the breast cancer gene regained glucose transport, preventing ROS accumulation, and recovered their ATP levels. The antioxidant-treated cells also survived, but by using fatty acids instead of glucose as an energy source. "Our results raise the possibility that antioxidant activity might allow early-stage tumor cells to survive where they otherwise would die from these metabolic defects," says Schafer.

The researchers are currently planning to test the effects of antioxidant genes, some of which are abnormally regulated in human tumors, and a wider range of antioxidants in animal models. They also plan on characterizing the metabolic consequences of matrix detachment in more detail. "Ultimately," Brugge says, "we want to understand enough about the metabolism of tumor cells so that new types of drugs can be designed to target them."

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Kidney dialysis machine 'small enough to be worn as a belt'

This really does seem to deserve that much over-used word "breakthrough"

Scientists have developed a kidney dialysis machine small enough to be worn as a belt which can allow patients to receive the treatment as they walk around. The breakthrough could potentially free thousands of patients from attending hospital every other day. More than 25,000 people in Britain need to have regular dialysis, usually around three times a week, because their kidneys do not function properly.

Described as “small and light enough to be wearable”, the battery-powered machine weighs around 10lb. Researchers hope that the device will give patients the freedom to have their treatment whenever and wherever they choose. Dr Victor Gura, from the David Geffen School of Medicine at UCLA, one of the team behind the new machine, said: “Our vision of a technological breakthrough has materialized in the form of a Wearable Artificial Kidney, which provides continuous dialysis 24 hours a day, seven days a week.”

While hospital patients have to receive a fairly intensive form of dialysis, because of the limited time available, the researchers hope that this machine can offer a gentler form, more akin to that provided naturally by the kidneys themselves.

The researchers are carrying out preliminary tests on the machine, including in patients who need dialysis. “However, the long-term effect of this technology on the well-being of dialysis patients must be demonstrated in much-needed clinical trials,” Dr Gura said. “Although successful, this is but one additional step on a long road still ahead of us to bring about a much-needed change in the lives of this population.”

Timothy Statham, chief executive of the National Kidney Federation (NKF) said that few patients would want round the clock dialysis but many would appreciate the extra freedom the device could offer. He added that many of the estimated two per cent of patients who had been able to have more regular dialysis, thorough machines in their own homes, had seen “remarkable results”.

The findings are published in the Clinical Journal of the American Society of Nephrology.

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